[unreadable] [unreadable] Few studies have examined the interrelations between oxidative stress, endothelial dysfunction, and coronary heart disease (CHD). Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthase (NOS), and has recently emerged as a potential novel risk marker for cardiovascular disease. The majority of ADMA is metabolized by the enzyme, dimethylarginine dimethylaminohydrolase (DDAH), and increased cellular oxidative stress inhibits DDAH activity in the tissues, which may lead to sustained levels of ADMA. Accumulation of ADMA and reduced NO synthesis leads to endothelial dysfunction and also initiates and promotes processes involved with atherogenesis. Plasma ADMA levels have been associated with several risk factors of CHD; however, data on the predictive value of ADMA, genetic variation in DDAH, and the prospective risk of CHD in men and women have thus far been limited. [unreadable] [unreadable] The overall goal of this K99/R00 career development proposal is to investigate plasma ADMA levels as a novel biochemical predictor of CHD among two large prospective cohort studies: the Nurses' Health Study (NHS) and the Health Professionals Follow-up Study (HPFS). Both studies have over 20 years of repeated dietary and lifestyle questionnaire data, blood samples collected from 32,826 women in NHS and 18,225 men in HPFS, and nested case-control studies with biological specimens previously archived among incident cases of nonfatal myocardial infarction or fatal CHD, and age and smoking matched controls. During the mentored K99 phase, Dr. Pai will complete advanced coursework; present and participate in seminars and conferences; continue to publish manuscripts on ongoing projects; meet regularly with her Mentor, and co-Mentor, an expert in endothelial and vascular biology; and begin preliminary work for completing the proposed specific aims. The specific aims of this R00 proposal are to: 1.) examine the prospective relationship between plasma ADMA and risk of incident CHD in nested case-control settings among men and women; 2.) utilize the existing prospective data to examine interrelations between lifestyle, dietary, and other health factors, and plasma ADMA to elucidate potential mechanisms; and 3.) examine the genetic variation in the DDAH gene with plasma ADMA levels and risk of CHD in both men and women. [unreadable] [unreadable] Lay description: Coronary heart disease is a major public health threat to U.S. men and women. ADMA is an emerging risk factor for CHD and may help improve risk prediction beyond what is currently understood. This proposal seeks to understand the influence of ADMA on CHD risk, its mediators, and also utilize these findings to improve overall risk prediction of cardiovascular disease. [unreadable] [unreadable] [unreadable] [unreadable]